1. Field of the Invention
The present invention relates to a latently-infected HIV-1 hematopoietic cell which maintains surface expression of CD4. The present invention further relates to methods of identifying anti-HIV-1 agents.
2. Background Information
The AIDS epidemic is a pressing health issue both in the United States and abroad. The retrovirus human immunodeficient virus type-1 (HIV-1) is the causative agent of AIDS. During the course of the AIDS disease there is normally an initial period of clinical latency which can extend for several years after infection with HIV-1 (Fauci, A. S. 1988, Science (Wash. D.C.), 239:617-622; Ranki et al., 1987, Lancet ii:589-593). During this period, HIV-1 may exist as a dormant or non-expressing provirus in a reservoir population of chronically infected cells (Hoxie et al., 1985, Science 229:1400-1402).
In Vitro studies with chronically HIV-1-infected tumor cell lines have shown that activation of the dormant provirus occurs when the correct stimuli are encountered (Clouse et al., 1989, J. Immunol. 142:431-438; Folks et al., 1987, Science 238:800-802; Folks et al., 1988, J. Immunol. 140:1117-1122; Folks et al., 1989, Proc. Natl. Acad. Sci. USA 86:2365-2368). Theoretically, a similar activation occurs with chronically infected cells in vivo and results in CD4 down-modulation, production of viral progeny, and cytopathic sequela (Fauci, A. S. 1988, Science (Wash. D.C.) 239:617-622).
The CD4+ T lymphocyte is the in vivo reservoir for HIV-1 (Psallidopoulos et al., 1989, J. Virol. 63:4626-4631; Schnittman et al., 1989, Science (Wash. D.C.) 245:305-308). Accordingly, CD4 surface expression apparently can be maintained during viral latency and expression of the virus is necessary to cause CD4 down-modulation. During HIV-1 expression, intracellular HIV-1 gp160/120-CD4 complexing (Crise et al., 1990, J. Virol. 64:5585-5593; Kawamura et al., 1989, J. Virol. 63:3748-3754; Koga et al., 1990, J. Virol. 64:4661-4671) and disruption of CD4 transcription (Hoxie et al., 1986, Science (Wash. D.C.) 234:1123-1127; Salmon et al., 1988, J. Exp. Med. 168:1953-1969) or translation (Yuille et al. 1988, J. Acquired Immune Defic. Syndr. 1:131-137) have been observed to explain this effect on surface CD4 levels. In addition, intracellular HIV-1 gp160/120-CD4 complexing has been implicated by some as a mechanism of viral cytopathicity (Hoxie et al., 1986, Science (Wash. D.C.) 234:1123-1127; Koga et al., 1990, J. Virol. 64:4661-4671), while other investigators have shown the cytopathic effect to be dependent upon the level of CD4 expression by the target cells (Koga et al., 1990, J. Immunol. 144:94-102; Rossi et al., 1986, Proc. Natl. Acad. Sci. USA. 83:4297-4301).
Although these facts are well established, it remains uncertain why CD4 expression is lost from the surface of chronically HIV-1 infected cell lines since they constitutively express only minimal amounts of HIV-1 proteins (Clouse et al., 1989, J. Immunol. 142:431-438; Folks et al., 1988, J. Immunol. 140:1117-1122; Hoxie et al., 1985, Science 229:1400-1402; Stevenson et al., 1987, J. Virol. 61:3741-3748). The inability of chronically HIV-1 infected cell lines to maintain surface CD4 expression has made them less than ideal modes of HIV-1 latency and unusable systems to explore the molecular mechanisms involved in CD4 modulation by HIV-1. The development of a latently HIV-1-infected cell model is critical for a full understanding of the virus and for the development of vaccines and therapeutic treatments. Such a cell model would ideally reproduce the HIV-1 induced CD4 modulation and serve as a physiologic model of the in vivo HIV-1 reservoir.